Blood Lead Level as Marker of Increased Risk of Ovarian Cancer in BRCA1 Carriers.

BRCA1 mutations substantially elevate the risks of breast and ovarian cancer. Various modifiers, including environmental factors, can influence cancer risk. Lead, a known carcinogen, has been associated with various cancers, but its impact on BRCA1 carriers remains unexplored. A cohort of 989 BRCA1 mutation carriers underwent genetic testing at the Pomeranian Medical University, Poland. Blood lead levels were measured using inductively coupled plasma mass spectrometry. Each subject was assigned to a category based on their tertile of blood lead. Cox regression analysis was used to assess cancer risk associations. Elevated blood lead levels (>13.6 µg/L) were associated with an increased risk of ovarian cancer (univariable: HR = 3.33; 95% CI: 1.23-9.00; p = 0.02; multivariable: HR = 2.10; 95% CI: 0.73-6.01; p = 0.17). No significant correlation was found with breast cancer risk. High blood lead levels are associated with increased risk of ovarian cancer in BRCA1 carriers, suggesting priority for preventive salpingo-oophorectomy. Potential risk reduction strategies include detoxification. Validation in diverse populations and exploration of detoxification methods for lowering lead levels are required.

Zinc and Its Antioxidant Properties: The Potential Use of Blood Zinc Levels as a Marker of Cancer Risk in BRCA1 Mutation Carriers.

BRCA1 mutations predispose women to breast and ovarian cancer. The anticancer effect of zinc is typically linked to its antioxidant abilities and protecting cells against oxidative stress. Zinc regulates key processes in cancer development, including DNA repair, gene expression, and apoptosis. We took a blood sample from 989 female BRCA1 mutation carriers who were initially unaffected by cancer and followed them for a mean of 7.5 years thereafter. There were 172 incident cases of cancer, including 121 cases of breast cancer, 29 cases of ovarian cancers, and 22 cancers at other sites. A zinc level in the lowest tertile was associated with a modestly higher risk of ovarian cancer compared to women with zinc levels in the upper two tertiles (HR = 1.65; 95% CI 0.80 to 3.44; p = 0.18), but this was not significant. Among those women with zinc levels in the lowest tertile, the 10-year cumulative risk of ovarian cancer was 6.1%. Among those in the top two tertiles of zinc level, the ten-year cumulative risk of ovarian cancer was 4.7%. There was no significant association between zinc level and breast cancer risk. Our preliminary study does not support an association between serum zinc level and cancer risk in BRCA1 mutation carriers.

Frequency of BRCA1 and BRCA2 mutations in ovarian cancer patients in South-East Poland.

BACKGROUND: Mutations in BRCA1 and BRCA2 genes are well-established risk factors of breast and ovarian cancer. In our former study, we observed that approximately 6% of unselected ovarian cancer patients in the region of Podkarpacie (South-East Poland) carry BRCA1 causative founder variants, which is significantly lower than in other regions of Poland. Therefore, it is deeply justified to do research based on the sequencing of whole BRCA1 and BRCA2 genes. METHODS: We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We performed BRCA1 and BRCA2 genes Next-Generation Sequencing study in all cases. RESULTS: Altogether, in 18 of 158 (11.4%) ovarian cancer patients with BRCA1 or BRCA2 pathogenic mutations were found. BRCA1 pathogenic variants were detected in 11 of the 158 (7.0%) ovarian cancer cases. 10 of 11 (91%) detected BRCA1 mutations were founder mutations, detectable with the standard test used in Poland. BRCA2 pathogenic variants were found in 7 of the 158 (4.4%) cases. No BRCA2 pathogenic variants were founder mutations. The median age of patients at the diagnosis of the 18 hereditary ovarian cancers was 57.5 years. CONCLUSIONS: The frequency of BRCA1 or BRCA2 gene mutation carriers among patients with ovarian cancer from the Podkarpacie region is comparable to other regions of Poland. However, a significantly higher percentage of BRCA2 gene mutations was observed, that were not detectable with a standard test for detection of founder mutations. Diagnostics based only on testing the BRCA1/2 Polish founder mutations is characterized by relatively low sensitivity in the case of ovarian cancer patients from South-East Poland and should be supplemented by NGS study, in particular of the BRCA2 gene.

Frequency of BRCA1 and BRCA2 causative founder variants in ovarian cancer patients in South-East Poland.

BACKGROUND: Causative variants in BRCA1 and BRCA2 are well-established risk factors for breast and ovarian cancer. In Poland, the causative founder variants in the BRCA1 are responsible for a significant proportion of ovarian cancer cases, however, regional differences in the frequencies of various mutations may exist. The spectrum and frequency of BRCA1/2 mutations between ovarian cancer patients have not yet been studied in the region of South-East Poland. METHODS: We examined 158 consecutive unselected cases of ovarian cancer patients from the region of Podkarpacie. We studied 13 Polish causative founder variants in BRCA1 (c.5266dupC, c.4035delA, c.5251C > T, c.181 T > G, c.676delT, c.68_69delAG, c.3700_3704delGTAAA, c.1687C > T, c.3756_3759delGTCT) and in BRCA2 (c.658_659delGT, c.7910_7914delCCTTT, c.3847_3848delGT, c.5946delT). RESULTS: A BRCA1 causative founder variants were detected in 10 of the 158 (6.3%) ovarian cancer cases. BRCA2 causative founder variants were not observed. The c.5266dupC mutation was detected in 6 patients, c.181 T > G mutation in 3 patients and the c.676delT mutation in 1 patient. The median age of diagnosis of the 10 hereditary ovarian cancers was 55.5 years of age. CONCLUSIONS: The frequency of 13 causative founder variants in Podkarpacie was lower than in other regions of Poland. Testing of three BRCA1 mutations (c.5266dupC, c.181 T > G, c.676delT) should be considered a sensitive test panel.

Case-control study analysis of DRD2 gene polymorphisms in drug addicted patients. / Analiza asocjacyjna polimorfizmów genu receptora dopaminy DRD2 u pacjentów uzaleznionych od narkotyków.

OBJECTIVES: The aim of the study was to determine relationships between the selected DRD2 gene polymorphisms and drug addiction. METHODS: One hundred drug abusers undergoing treatment were recruited from the inpatient psychiatric centers in Poland. All participants were screened by means of the clinical interview SSAGA to describe the clinical picture. In the second part of the study, participants were examined using psychometric tools assessing selected psychopathological features. After that, blood samples were collected for a DNA isolation. The following DRD2 single nucleotide polymorphisms (SNPs) of the dopamine gene were genotyped: rs1800498 polymorphism of DRD2 gene (NC_000011.10:g.113420866G>A, GRCh38.p7); rs1079597 polymorphism of DRD2 gene (NC_000011.10:g.113425564C>T, GRCh38.p7); rs1076560 polymorphism of DRD2 gene (NC_000011.10:g.113412966C>A, GRCh38.p7). RESULTS: The rs1800498 polymorphism has shown an association with drug abuse in which a higher frequency of the allelic T form was observed in the whole group of patients and selected subgroups with concomitant opiates or cannabis abuse history when compared with the controls. CONCLUSIONS: In the presented study, one of selected polymorphisms of DRD2 gene, revealed to be correlated with substance use disorder (at the limit of statistical significance), which could suggest its impact on dependence endophenotype. The presented research was a pilot study, so it requires replication on a larger group of patients to verify and confirm obtained outcomes.

Case control study of ANKK1 Taq 1A polymorphism in patients with alcohol dependence classified according to Lesch's typology.

OBJECTIVE: The aim of this study was to examine the association between the Taq 1A polymorphism of the ANKK1 gene in homogeneous subgroups of patients with alcohol dependence syndrome divided according to Lesch's typology. MATERIAL/METHODS: DNA was provided from alcohol-dependent (AD) patients (n = 373) and healthy control subjects (n = 168), all of Polish descent. The history of alcoholism was obtained using the Polish version of the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). Samples were genotyped using the PCR method. RESULTS: We found no association between alcohol dependence and ANKK1 Taq 1A polymorphism. CONCLUSIONS: Lesch's typology is a clinical consequence of the disease, and its phenotypic description is too complex for simple genetic analysis.

Analysis of the Relationship between Estradiol and Follicle-Stimulating Hormone Concentrations and Polymorphisms of Apolipoprotein E and LeptinGenes in Women Post-Menopause.

BACKGROUND: Menopause is the permanent cessation of menstruation due to loss of ovarian follicular activity. A review of the available literature indicates that correlations between the changes that take place in a woman's body after menopause and different genetic variants are still being sought. METHODS: The study was conducted in 252 women who had completed physiological menopause. The women were divided into groups according to the time elapsed since menopause. The total concentrations of estradiol and follicle-stimulating hormone were determined by means of electrochemiluminescence. The apolipoprotein E (APOE) and lepitn (LEP) genotypes were determined by real-time PCR and polymerase chain reaction-restriction fragment length polymorphism, respectively. RESULTS: We observed that people with the APOE3/E3 genotype entered menopause insignificantly later compared to other genotypes. Additionally, in the group of patients with the APOE3/E3 genotypes, differences in the E2 concentration were significantly related to the time since their last menstruation. There is no association found in the literature between these polymorphisms of the LEP gene and hormones. CONCLUSIONS: To date, attempts to formulate a model describing the association between E2 and FSH concentration with the polymorphisms of various genes of menopause in women have not been successful. This relationship is difficult to study because of the number of nongenetic factors. Environmental factors can explain variation in postmenopausal changes in hormone levels.

Functional polymorphism of matrix metalloproteinase-9 (MMP9) gene is not associated with schizophrenia and with its deficit subtype.

BACKGROUND: The deficit subtype of schizophrenia is hypothesized to constitute a pathophysiologically distinct subgroup of schizophrenia patients suffering from enduring, idiopathic negative symptoms and various neuropsychological deficits. Matrix metalloproteinases (MMPs) are extracellularly acting endopeptidases the substrates of which are matrix and adhesion molecules. Recently, MMP9 has been shown to be involved in various forms of synaptic plasticity, learning and memory consolidation. The primary aim of the present study was to evaluate associations between the functional MMP-9 -1562C/T gene polymorphism and the deficit and non-deficit subtypes of schizophrenia. METHODS: The study was conducted between 2009 and 2012. Deficit schizophrenia was diagnosed using the SDS. The sample consisted of 468 patients, Caucasians, of Polish descent with ICD 10 diagnosis of schizophrenia: 189 [51% males] were included in a non-deficit subgroup, 279 patients [53% males] were included in a deficit subgroup. The control group consisted of 532 subjects, Caucasians, of Polish descent [51% males]. MMP-9 -1562C/T gene polymorphism was genotyped using the fluorescence resonance energy transfer (FRET) method and the Light Cycler System 2.0. RESULTS: The frequencies of genotypes and alleles did not differ between the schizophrenia patients and control group. The deficit and non-deficit patients did not differ in terms of the genotype and allele frequencies. No differences were found in genotype and allele frequencies between the deficit patients and the controls and between the non-deficit patients and the controls. CONCLUSION: We found no evidence for the association between the functional MMP-9 -1562C/T gene polymorphism and deficit/non-deficit subtypes of schizophrenia.

DAT1 methylation changes in alcohol-dependent individuals vs. controls.

INTRODUCTION: The dopaminergic system plays a crucial role in the development of alcohol dependence. Regulation of the extracellular dopamine concentration is driven by dopamine transporter. Both, the expression and function of dopamine transporter, are influenced by chronic alcohol intake. Dopamine transporter (DAT) gene is also supposed to be differentially methylated in alcohol-dependent patients than in controls. MATERIAL AND METHODS: DNA was extracted from peripheral blood leukocytes. We analyzed the methylation status in 23 CpG islands of DAT gene promoter in alcohol dependent subjects (n = 171) and control (n = 160) group. RESULTS: No statistical differences in the general frequency of DAT CpG islands was revealed between patients (altogether 175 methylated islands) and control subjects (170 methylated islands (p = 0.86). However it was revealed that one of analyzed positions is significantly more often methylated in control subjects than in alcohol dependent individuals (p = 0.0296). CONCLUSION: Further subsequent studies are necessary to determine whether the methylation change of one (out of 23) CpG site results in DAT expression changes.

Monoamine oxidase a promoter variable number of tandem repeats (MAOA-uVNTR) in alcoholics according to Lesch typology.

BACKGROUND: The aim of this study was to examine the association between the MAOA-uVNTR gene polymorphism in a homogeneous subgroups of patients with alcohol dependence categorized according to Lesch's typology. METHODS: DNA was provided from alcohol dependent (AD) patients (n=370) and healthy control subjects (n=168) all of Polish descent. The history of alcoholism was obtained using the Polish version of the Semi-Structured Assessment for the Genetics of Alcoholism (SSAGA). Samples were genotyped using PCR methods. RESULTS: We found no association between alcohol dependence and MAOA gene polymorphism. CONCLUSIONS: Lesch typology is a clinical consequence of the disease and its phenotypic description is too complex for a simple genetic analysis.

Association and family studies of DRD2 gene polymorphisms in alcohol dependence syndrome.

INTRODUCTION: The human dopamine receptor 2 gene DRD2 plays a central role in susceptibility to Alcohol Dependence Syndrome (ADS). The aim of this study was to evaluate 3 single nucleotide polymorphisms: D2 (rs1076560), Tag1D (rs1800498), Tag1B (rs1079597) located in dopamine receptor 2 DRD2 gene and its role in alcohol dependence. MATERIAL AND METHODS: DNA was provided from alcohol dependent (AD) patients (n=171) and healthy control subjects (n=160) all of Polish descent. The history of alcoholism was obtained using the Polish version of the SSAGA (Semi-Structured Assessment for the Genetics of Alcoholism). We conducted case-control association study and transmission disequilibrium test (TDT). Samples were genotyped using real-time PCR method. RESULTS: We did not confirm the association between studied polymorphisms and alcohol dependence syndrome. TDT reveled an adequate transmission of both alleles in the group of alcohol families. CONCLUSIONS: The lack of association of studied polymorphisms and ADS does not preclude its participation in the pathogenesis. Further research is needed to determine the actual contribution of DRD2 gene in the pathogenesis of alcoholism.

Suicidal behavior and haplotypes of the dopamine receptor gene (DRD2) and ANKK1 gene polymorphisms in patients with alcohol dependence--preliminary report.

Suicide is a significant public health issue and a major cause of death throughout the world. According to WHO it accounts for almost 2% of deaths worldwide. The etiology of suicidal behavior is complex but the results of many studies suggest that genetic determinants are of significant importance. In our study,--we have analyzed selected SNPs polymorphisms in the DRD2 and ANKK1 genes in patients with alcohol dependence syndrome (169 Caucasian subjects) including a subgroup of individuals (n = 61) who have experienced at least one suicide attempt. The aim of the study was to verify if various haplotypes of selected genes, comprising Taq1A, Taq1B, and Taq1D single nucleotide polymorphisms (SNP), play any role in the development of alcohol dependence and suicidal behavior. The control group comprised 157 unrelated individuals matched for ethnicity, gender,- and age and included no individuals with mental disorders. All subjects were recruited in the North West region of Poland. The study showed that alcohol dependent subjects with a history of at least one suicidal attempt were characterized by a significantly higher frequency of the T-G-A2 haplotype when compared to individuals in whom alcohol dependence was not associated with suicidal behavior (p = 0.006). It appears that studies based on identifying correlation between SNPs is the future for research on genetic risk factors that contribute to the development of alcohol addiction and other associated disorders. To sum up, there is a necessity to perform further research to explain dependencies between the dopaminergic system, alcohol use disorders and suicidal behavior.

[The analysis of the polymorphic variations of the dopamine gen transporter (DAT1) and the serotonin transporter (5-HTTLPR) in patients with alcohol dependence syndrome with inclusion of the phenotypic feature of sweet liking preference]. / Analiza polimorficznych wariantów genu transportera dopaminy DAT1 i transportera serotoniny 5-HTTLPR u pacjentów z zespolem zaleznosci alkoholowej z uwzglednieniem fenotypowej cechy preferencji smaku slodkiego.

OBJECTIVES: The purpose of this study was to determine the relationship between sweet-liking phenotype and the variation of the gene sequence of the dopaminergic and serotonergic system. METHODS: The study recruited 100 probands. The participants were interviewed for addiction (SSAGA-Semi Structured Assessment for the Genetics of Alcoholism) and assessed with the questionnaires: MMSE, Beck Depression Inventory and Hamilton Anxiety, Snaith-Hamilton Pleasure Scale. The taste was analyzed with tests to assess sensitivity to sweet taste and also smell tests were performed. Patients preferring the highest glucose volumes were called sweet likers. Statistical analyses were performed (SPSS- Statistical Package for the Social Sciences). RESULTS: Links between sweet liking phenotype and polymorphic variant of DAT1 gene were determined. The presence of DAT1 9/10 genotype increased three fold time sweet liking phenotype (p = 0.015, odds ratio-3.00), the presence of DAT1 10/10 decreased two fold time the chance being sweet liker (p = 0.051, odds ratio-0.43). Genotype 10/10 was significantly more common among sweet dislikers 10/10 (68.18% vs 47.92%) i 9/9 (6.82% vs 2.08%). CONCLUSIONS; A genetically significant association between the presence of 9/10 DAT1 VNTR genotype and a sweet-liking phenotype in probands was determined.

The effect of selected polymorphisms of the dopamine receptor gene DRD2 and the ANKK-1 on the preference of concentrations of sucrose solutions in men with alcohol dependence.

BACKGROUND: The aim of the study was to determine the influence of DRD2 gene polymorphisms in exon 8 G/A (rs 6276) in the promoter region -141 C Ins/Del (rs1799732) and the influence of ANKK-1 gene Taq-1A polymorphism (rs 1800497) on the preference of increasing sucrose concentrations in men with alcohol dependence. SUBJECTS AND METHODS: 63 male patients with alcohol dependence were genotyped for the above polymorphisms. Their preference for increasing sucrose concentrations was tested and their taste intensity perception of sucrose solutions was assessed. The patients were tested with the 'Sniffin' Sticks' olfactory test. RESULTS: We found a statistically significant association between some alleles of ANKK 1 gene Taq 1A polymorphisms and sucrose preference in the subjects. The A1 Taq 1A allele determined hedonistic response to the two highest concentrations of sucrose. No association was found regarding the other two polymorphisms (in the promoter region and in the exon 8 of the DRD2 gene). CONCLUSIONS: Study results suggest Taq-1A polymorphism plays a role in the preference to high concentrations of sucrose and its potential association with alcohol dependence pathogenesis.

BDNF rs 6265 polymorphism and COMT rs 4680 polymorphism in deficit schizophrenia in Polish sample.

BACKGROUND: Deficit schizophrenia (DS) is distinguished from the group of schizophrenic psychoses based on the presence of primary negative symptoms. It differs from nondeficit (NDS) forms of schizophrenia in dimensions such as risk factors, family history, course of illness and neurobiological differences. The aim of the study was assessment of a potential association of the investigated polymorphisms of the brain-derived neurotrophic factor (BDNF) and catechol-O-methyltransferase (COMT) genes with the deficit syndrome in schizophrenia. METHODS: A cohort of 200 patients with schizophrenia (81 DS and 119 NDS subjects) and a group of 100 control subjects matched for ethnicity, sex and age were recruited. Somatic and psychometric assessment were conducted as well as structured interview about the influence of adverse biological, family and social factors. Genetic analysis of the BDNF (Val66Met) rs6265 and the COMT (Val158Met) rs4680 polymorphisms was performed. RESULTS: We found significant differences between DS and NDS in rs4680 COMT genotype distribution: more homozygous Val/Val were found (31 vs. 17%) in the NDS compared to the DS subgroup. No associations were found between the investigated polymorphisms of the BDNF gene and the presence of schizophrenia either in DS and NDS subgroups. CONCLUSION: The analysis of the COMT rs4680 polymorphism in the present DS and NDS study shows that some genetic factors may be relevant in analyzing the reasons for the differentiation of schizophrenic subtypes.

Influence of DRD2 and ANKK1 polymorphisms on the manifestation of withdrawal syndrome symptoms in alcohol addiction.

BACKGROUND: We investigated the relationship between withdrawal syndrome symptoms and dopamine receptor 2 DRD2 gene polymorphisms-141 C I/D (rs1799732) exon 8 G/A (rs6276) and ANKK1 (Ankyrin Repeat and Kinase Domain Containing 1) gene polymorphism Taq1A (rs1800497). MATERIAL: A total number of 213 patients who met the ICD 10 criteria for given phenotypes were enrolled in the study. Those phenotypes included: dissocial personality disorder, early onset, alcohol withdrawal syndrome with seizures, alcohol withdrawal syndrome with delirium tremens, and alcohol withdrawal syndrome with seizures and delirium tremens. RESULTS: Our results show statistically significant associations between SNP in exon 8 A/G in the DRD2 gene and alcohol withdrawal syndrome with seizures, and between SNP in promoter -141 C I/D in the DRD2 gene and early onset of alcohol dependence (AD). The A/A genotype in exon 8 A/G polymorphism seems to be a positive predictive factor for the presence or the lack of seizures in alcohol withdrawal syndrome. The A/G genotype is possibly a protective factor for this AD phenotype. CONCLUSIONS: These results suggest that both investigated DRD2 polymorphisms have an impact on the AD phenotype. The findings of the presented study reconfirm that dopamine receptor 2 gene polymorphisms are associated with alcohol addiction and alcohol withdrawal syndrome.

Influence of DRD2 and ANKK1 genotypes on apomorphine-induced growth hormone (GH) response in alcohol-dependent patients.

BACKGROUND: D(2) receptor function can be assessed by growth hormone (GH) response to apomorphine. Several association studies between dopamine receptor polymorphisms and results of the apomorphine challenge test with normal and alcohol-dependent subjects yielded inconsistent results. In this pilot study, we tested polymorphisms from the DRD2 region for GH response to apomorphine challenge in more detail. METHODS: Apomorphine challenge tests measuring GH responses on 5 time points were performed on day 1 of alcohol detoxification in 43 patients with alcohol dependence; patients were genotyped for 11 polymorphisms including DRD2, ANKK1, NCAM1 and TTC12. RESULTS: Associations (p<0.05) were found for ANKK1 (rs11604671, rs1800497) and DRD2 (rs6276, rs1076560), which are located on adjacent chromosomal positions. Consistent with PET studies suggesting a reduced D(2) receptor availability in patients carrying the ANKK1 rs1800497 T polymorphism (formerly known as DRD2 TaqI A1) we found a reduced GH response to apomorphine in those subjects. CONCLUSION: This has been the first study showing significant associations between apomorphine-induced GH response and SNPs in DRD2 and ANKK1 in alcohol-dependent patients. In this respect, our preliminary results are in line with other reports which suggested that DRD2 and ANKK1 polymorphisms influence D(2) receptor availability and signal transduction in the dopaminergic pathways. Small sample size in our study limits the generalizability of our results.